Bone is the second most common tissue to be transplanted after blood. The most reliable method to repair bone defects is to use autogenous bone, i.e. bone taken from another site in the body. However, problems may occur at the second surgical site from where the graft is taken. To avoid this extra trauma, allografts can be used, i.e. bone graft between individuals of the same species. Allografts have a lower osteogenic capacity than autografts and the rate of new bone formation might be lower. They also have a higher resorption rate, a larger immunogenic response and less revascularization of the recipient. Allografts must also be controlled for viruses since they can transfer, for example, HIV and hepatitis. The use of allografts is now the most common method for bone transplantation and repairing of bone defects. To solve the problems of supply, unpredictable strength and risk of infection, synthetic bone substitutes have become a realistic alternative. Thus, the demand for and use of synthetic bone substitutes is increasing rapidly.
Ceramic based synthetic bones substitutes can be divided into two main types. One type is based on calcium phosphate as the setting component and these are referred to as calcium phosphate cements. Another type is based on calcium sulfate as the setting component. The most important advantage with calcium sulfate is its excellent biocompatibility. The drawbacks with pure calcium sulfate bone substitutes are the rapid resorption and low strength, which make them less useful in larger or non-contained defects and when the fracture healing exceeds 4-6 weeks.
Bone Support AB has developed hardenable and injectable calcium sulfate based bone substitutes with the powder phase comprising approximately 40 wt % sintered hydroxyapatite (HA) (Ca10(PO4)6(OH)2) and approximately 60 wt % calcium sulfate hemihydrate, CSH, (CaSO4−½ H2O). Of the two components, only CSH will set during the setting process. The HA powder will remain un-dissolved. The liquid phase of the injectable paste consists of an aqueous solution that for some of the products contain iohexol molecules to enhance the radiopacity of the material (WO2003/053488). If only the calcium sulfate was present in the bone substitute, there would be a complete material resorption within approximately 4-6 weeks. However, since there is also HA in the sample, this will slow down the calcium sulfate resorption. In addition, the HA in the sample will remain at the site of implantation for a longer time due to its high crystallinity and low solubility.
The setting time of the hardened bone substitute from the paste is an important parameter for determining their applicability as bone substitutes. Gillmore needles (ASTM C266) are often used to measure the initial setting time (IST) and the final setting time (FST) of cements. In a clinical situation the IST and FST can be interpreted such that the cement should be implanted before IST is reached and the wound is ready to be closed after the FST. IST times around 5-25 min typically allows sufficient time for the cement to be injected or molded, and FST times around 10-40 minutes are usually acceptable for clinical use. It is preferred to have IST times around 5-15 minutes, such as less than 10 minutes. Different products have different specifications since they will be used for different applications. Other ways of determining the applicability of a hardenable bone substitute are known in the art.
For a variety of applications, it is desirable to be able to mix different additives with bone substitutes, where calcium sulfate is a setting component. Bone substitutes comprising an additive such as for example an antibiotic would be desirable to have in order to be able to treat or prevent different disorders, e.g. osteomyelitis (bone infections). However, it has been found that the addition of some bioactive agents, such as antibiotics, retard the setting of the bone substitute in such a manner that the setting time exceeds clinically acceptable values. It has also been found that not only additives, but also basic components of the bone substitute, such as HA, may have a negative effect on the setting properties. It has surprisingly turned out, that the rate of the CSH hydration necessary for setting of the calcium sulfate in a HA containing calcium sulfate based bone substitute is highly dependent on the properties of the HA.